Protein synthesis is carried out by an elaborate translation complex, which is composed of a ribosome, accessory protein factors as well as mRNA and charged tRNA molecules. Like DNA and RNA synthesis, protein synthesis can be divided into initiation, chain elongation and termination stages. Initiation involves the assembly of the translation complex at the start codon in the mRNA. During polypeptide-chain elongation, the ribosome and associated components move in the 5′ to 3′ direction along the template mRNA. The polypeptide is synthesized from the N-terminus to the C-terminus. Finally, when synthesis of the protein is complete, the translation complex disassembles in a separate termination step. An important part of this disassembly is the release of the ribosome from the mRNA, which is signaled by a stop codon.
Catalysis of peptide bond formation requires the precise juxtaposition by the ribosome of the acceptor ends of the amino acid-charged tRNA's bound in the peptidyl site (i.e., P site) and aminoacyl site (i.e., A site) of its “active site”. This activity represents the essential enzymatic activity of the ribosome and is referred to as the “peptidyl transferase activity,” an integral component of the large subunit of all ribosomes characterized to date. Studies of bacterial ribosomes have identified the essential active site constituents of the peptidyl transferase activity as a few ribosomal protein subunits and the 23S rRNA. As the integrity of the latter is essential for enzymatic activity, it is assumed that it plays a direct role in the catalysis of peptide bond formation acting as a so-called ribozyme.
Many diseases involve foreign or aberrant host proteins, for example, viral infections involve the synthesis of viral proteins, e.g., capsid proteins. A variety of agents are presently used to combat viral infection. These agents include interferon, which is a naturally-occurring protein having some efficacy in combat of certain selected viral diseases. In addition, agents such as AZT are used in the combat of an immunodeficiency disease, referred to commonly as AIDS, caused by the virus HIV-1.
Given the large number of drugs available for treating infections caused by more complex organisms such as bacteria, it is remarkable how few drugs are available for treating the relatively simple organisms known as viruses. Indeed, most viral diseases remain essentially untreatable. The development of new antiviral chemotherapeutics is resource- and time-intensive. The difficulties encountered in drug treatment of most infections pale when compared to viral infections. For example, it is at least theoretically (and often in practice) possible to attack a bacterium without harming the host. Unlike bacteria however, viruses replicate inside cells and utilize cellular machinery of the host for replication. As a result, development of antiviral therapeutics often represents a compromise between preferable killing, or at least arresting replication of, the virus, and not harming the host, or at worst, doing only minimal damage which can be justified by the potential gain (Drug and Market Development, Vol 3. No. 9, pp. 174-180 (Feb. 15, 1993)).
It is now generally recognized that an important challenge for small molecule drug discovery is the identification of novel druggable targets (Hopkins A-L, Groom C-R (2002) The druggable genome. Nat Rev Drug Discov. 1:727-730). Conventional targets appear to have largely been exhausted, and it can be argued that various highly anticipated methods in recent years have disappointed, in that many of the targets they are identifying are of questionable druggability (Goff S-P (2008) Knockdown screens to knockout HIV-1. Cell 135:417-420). How then does one find the likely highly unconventional novel druggable targets of the future?